Potent Nucleotide Inhibitors of Ecto-5'-Nucleotidase (CD73)

Novel, small molecule nucleotide derivatives have been developed containing either a purine or pyrimidine nucleobase that competitively block the enzyme CD73, or ecto-5'-nucleotidase.  CD73 converts extracellular AMP to adenosine, the native activator of 4 subtypes of adenosine receptors.  CD73 has been shown to be upregulated around tumors leading to excess production of adenosine.  The use of CD73 inhibitors in conjunction with cancer immunotherapy is being explored in preclinical research and clinical trials.  Blocking this enzyme can greatly reduce immunosuppressive adenosine in the tumor microenvironment.  Therefore, combined therapy is expected to be more effective than cancer immunotherapy alone.

Previously, adenine nucleotides have been used as CD73 inhibitors in research, but these can lead to off-target activity at purinergic receptors. Thus, the ability to potently inhibit the enzyme using a different nucleobase derivative can provide greater specificity for the target in comparison to earlier inhibitors.